Using BCG Vaccine to Enhance Non-specific Protection of Senior Citizens During the COVID-19 Pandemic. A Randomized Clinical Trial.
试验速览
- 阶段
- 3 期
- 状态
- 已完成
- 入组人数
- 1,700
- 试验地点
- 2
- 主要终点
- Acute Infection
研究概览
简要总结
Background: The virus SARS-CoV-2 has spread rapidly throughout the world. Seniors are at high risk of severe COVID-19 when infected. Bacille Calmette-Guérin (BCG) is a vaccine against tuberculosis, with protective non-specific effects against other infections; significant reductions in morbidity and mortality have been reported, and a plausible immunological mechanism has been identified: "trained innate immunity". The investigators hypothesize that BCG vaccination can reduce the risk of COVID-19 and other infections among senior citizens during the COVID-19 pandemic.
Objectives: Primary objective: To reduce senior citizens' risk of acute infection during the COVID-19 pandemic. Secondary objectives: To reduce senior citizens' risk of SARS-CoV-2 infection during the COVID-19 pandemic. To reduce senior citizens' risk of self-reported respiratory illness during the COVID-19 pandemic.
Study design: A placebo-controlled randomized trial. Study population: 1900 seniors 65 years of age or above. Intervention: Participants will be randomized 1:1 to intradermal administration of a standard dose of BCG vaccine or placebo (saline).
Outcomes: Primary outcome: "Acute infection" identified either by a doctor, antibiotics use, hospitalization, or death due to infection. Secondary outcomes: Verified SARS-CoV-2 infection and self-reported respiratory illness.
With an expected incidence of "acute infection" of 20%, the trial can show a 25% risk reduction in the the intervention group versus the placebo group by including a total of 1900 individuals, 950 individuals in each group.
Risk for participants and impact: Based on previous experience and randomized controlled trials in adult and elderly individuals, the risks of BCG vaccination are considered low. If BCG can reduce the risk of acute infection in seniors by 25% it has tremendous public health importance, both during the COVID-19 pandemic and overall.
详细描述
INTRODUCTION One of the most recognized consequences of aging is a decline in immune function, so-called "immunosenescence". Vaccination is the most effective prophylactic intervention for infectious diseases, but due to immunosenescence, the efficacy of vaccines decreases with increasing age.
Due to immunosenescence, severe infections are more common in the elderly. Not least during the COVID-19 pandemic, it has become clear that elderly people are particularly susceptible to severe COVID-19. Strategies to strengthen senior citizens' immune system are urgently warranted.
Bacillus Calmette-Guérin (BCG) was developed as a childhood vaccine against tuberculosis, but our group has shown that it can protect against death from other infections, i.e. it has what the investigators have called non-specific effects (NSEs). In clinical studies, BCG vaccination was associated with decreased child mortality, mainly as a result of reduced neonatal sepsis and respiratory infections. In a meta-analysis commissioned by the World Health Organization (WHO), BCG was associated with a 42% (95%CI: 24-55%) reduction in child mortality.
NSEs of BCG are not limited to children. An Indonesian trial with 34 subjects aged 60-75 years reported that compared with placebo, consecutive BCG vaccination for 3 months reduced the incidence of acute upper respiratory tract infections by 80% (95% confidence interval (CI)=22-95%). In a very recent clinical trial in Greece, BCG vs. placebo to senior citizens at discharge from the hospital was associated with a significant decrease in time to first infection (p: 0.035). The incidence of new infections was 42.3% (99% CIs 31.9 53.4%) in the placebo group and 25.0% (95% CIs (16.4-36.16%) in the BCG group; most of the protection was against respiratory tract infections (odds ratio 0.20; p: 0.001). No difference in the frequency of adverse effects was found between groups. These data show that BCG vaccination is safe and can protect the elderly against infections.
Immunological studies have now provided an explanation for the observed NSEs of BCG: BCG induces epigenetic and metabolic reprogramming of innate immune cells such as myeloid cells and Natural Killer cells, leading to an increased antimicrobial activity, a process termed 'trained immunity'.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Prevention
- 盲法
- Double (Participant, Outcomes Assessor)
盲法说明
Participants will be blinded to treatment. The physicians administering the BCG vaccine or placebo will not be blinded.
入排标准
- 年龄范围
- 65 Years 至 110 Years（Older Adult）
- 性别
- All
- 接受健康志愿者
- 是
入选标准
- •In order to be eligible to participate in this study, a subject must meet the following criteria: ≥65 years old.
排除标准
- •Known allergy to (components of) the BCG vaccine or serious adverse events in relation to prior BCG administration
- •Previous Mycobacterium tuberculosis (M. tuberculosis) infection or known active or latent infection with M. tuberculosis or other mycobacterial species
- •Previous confirmed COVID-19 infection
- •Fever (>38 C) within the past 24 hours or suspicion of active viral or bacterial infection
- •Vaccination with other live attenuated vaccine within the last 4 weeks
- •Severely immunocompromised subjects. This exclusion category comprises:
- •Subjects with known infection with the human immunodeficiency virus (HIV)
- •Subjects with solid organ transplantation or bone marrow transplantation
- •Subjects under chemotherapy
- •Subjects with primary immunodeficiency
- •Treatment with any anti-cytokine therapy within the last year
- •Treatment with oral or intravenous steroids defined as daily doses of 10 mg prednisone or equivalent for longer than 3 months
- •Active solid or non-solid malignancy or lymphoma within the prior two years
- •Subjects who do not have access to e-Boks.
结局指标
主要结局
Acute Infection
时间窗: 12 months after inclusion
The primary outcome was a composite outcome of acute infection (recurrent events) defined as "infection attended by a physician", "use of antibiotics", "hospitalisation due to infection", or "death due to infection". All subcomponents were also analysed separately.
次要结局
- Self-reported Respiratory Symptoms (Recurrent Events)(12 months after inclusion)
- Verified SARS-CoV-2 Infection (First Event)(12 months after inclusion)
- All-cause Hospitalisation (First Event)(12 months from inclusion.)